PN6047; a potent and selective delta opioid receptor agonist, effective against chronic pain
Therapeutic target Chronic pain varies from mild discomfort to the worst pain imaginable. In the UK, the total cost of chronic pain is estimated at around 10 billion per year with about 20% attributed to neuropathic pain; osteoarthritis treatment costs about 128 million per annum. Incidence is high and is increasing with aging populations. Why target delta (δ) opioid receptors for treating chronic pain? 2
Location of δ-opioid receptors (DOR) in pain pathway Perception of pain; control of emotion Modulation of pain signals Transmission of pain signals Generation of pain signals DORs are located at key points in the pathway to reduce pain, especially when it becomes chronic
Other reasons for targeting delta opioid receptors for treating chronic pain? Existing therapies (opioids, antidepressants, Na + channel blockers) only partly effective in neuropathic pain, OA etc. Strong opioids (morphine-like) work well in acute pain but are non-selective for all opioid receptors (μ, δ, κ). Side effects ; nausea, respiratory depression, itching, constipation largely due to μ receptor activation. Analgesic tolerance can be detected within 12-24 hrs of morphine administration.
DOR knockout mice show only subtle modification of acute pain thresholds but display increased neuropathic and inflammatory pain. Therefore, DORs should be effective in these conditions. Original DOR agonists showed few signs of unwanted side effects (constipation, respiratory depression) in pre-clinical testing. Why develop biased DOR agonists?
What is agonist bias? DOR agonist Conventionally, thought that all receptor agonists could activate whole spectrum of possible signalling pathways ; now clear that different agonists induce particular receptor conformations leading to distinct signalling outcomes; some beneficial some not. This is agonist bias.
PharmNovo has developed a series of compounds showing a range of agonist effects on different signalling systems. PN6047 is a full agonist regarding camp inhibition but partial regarding β-arrestin recruitment and DOR internalization. This is a combination of properties that we believe to be optimal for clinical effects.
PN6047 In vivo analgesia Analgesic effect of PN6047 in rat model of neuropathic pain PN6047 is potent (half maximal effect at ~ 1 mg/kg oral). PN6047 is very selective; selectivity at delta receptors >20,000- fold (δ vs μ). In comparison, morphine is 50-fold selective for μ vs δ.
% c o n tr o l h y p e r s e n s itiv ity PN6047 P N 6 0 4 7 (3 m g /k g, p.o.) r e d u c tio n in m e c h a n ic a l h y p e r a lg e s ia in n e u r o p a th ic m o u s e m o d e l In vivo analgesia 1 5 0 1 0 0 P N 6 0 4 7 C o n tro l 5 0 0 0 5 1 0 1 5 2 0 2 5 T im e o f tr e a tm e n t (d a y s ) Marked tolerance is a property of non-selective opioids. No development of tolerance to the analgesic effects of PN6047 over 3 weeks of repeated daily treatment in a mouse sciatic nerve ligation model of neuropathic pain.
Statistical analysis, unpaired t-test using Prism A major negative property of early DOR agonists was proconvulsant activity. In doses up to 20 mg/kg, PN6047 produced no seizures and did not change the seizure response to pentylenetetrazole (PTZ) in mice. Dose (mg/kg) PTZ induced seizures - Myoclonus 50 40 30 20 10 0 Vehicle (n=12) PN6047 (n=11)
Non-selective opioids cause problematic constipation; in rats and mice PN6047 does not. No changes in body weight on repeated treatment. No behavioural changes. Conclusion; PN6047 is well tolerated in animal tests and produces no toxic effects, with safety dosing based on 50 times the therapeutic dose. Prediction of human ADME/PK-properties is favourable - moderate oral bioavailability, t1/2 and CNS distribution. Estimated human dose range; 2-20 mg twice daily.
Other therapeutic potential for PN6047? Anxiety and depression Some other selective DOR agonists (e.g. SNC80, NIH11082, UFP512, ADL5859) are antidepressant and anxiolytic in preclinical models comparable to SSRIs and TCAs. Neuroprotection DOR antagonism prevents neurodegeneration in the retina induced by elevation of intraocular pressure. Potential in Alzheimer s, Parkinson s Diseases. 12
In summary Why is PN6047 potentially important? Can be a safe and effective treatment for chronic pain. Large patient populations. Great potential in related CNS diseases. Lacks side effects (a huge burden for morphinelike opioids). PN6047 has the potential to be a first-line chronic pain medicine. 13
PN6047 development PharmNovo now give the opportunity for a Pharma, in a good industrial collaboration, to work with us and take PN6047 into clinical testing.